Trial Outcomes & Findings for A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis (RE-SPECT CVT) (NCT NCT02913326)

Last Updated: 2019-08-15

Results Overview

Composite of the percentage of participants with MBE according to ISTH criteria and VTE (recurring cerebral venous thrombosis (CVT); deep venous thrombosis (DVT) of any limb, pulmonary embolism (PE), splanchnic vein thrombosis) in full observation period. All components were adjudicated in a blinded manner. Major bleeds were defined according to the ISTH definition of a major bleed, as follows: * Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or * Bleeding associated with a reduction in haemoglobin of at least 2 grams/deciLitre (1.24 millimole/Litre) within 24 h, or leading to transfusion of 2 or more units of blood or packed cells and/or * Fatal bleed

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

120 participants

Primary outcome timeframe

From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.

Results posted on

2019-08-15

Participant Flow

This is a randomised, open-label, exploratory trial with blinded endpoint adjudication (PROBE \[prospective, randomised, open-label, blinded endpoint\] design), comparing efficacy and safety of oral dabigatran etexilate versus oral warfarin in patients with cerebral venous and dural sinus thrombosis over a 24-week period.

All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensure that they (all participants) met all inclusion/exclusion criteria. Participants were not to be randomised to trial treatment if any one of the specific entry criteria were not met.

Participant milestones

Participant milestones
Measure	Dabigatran Etexilate Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Overall Study STARTED	60	60
Overall Study COMPLETED	59	58
Overall Study NOT COMPLETED	1	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Dabigatran Etexilate Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Overall Study Reason not listed	0	1
Overall Study Lost to Follow-up	0	1
Overall Study Adverse Event	1	0

Baseline Characteristics

A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis (RE-SPECT CVT)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dabigatran Etexilate n=60 Participants Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=60 Participants Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.	Total n=120 Participants Total of all reporting groups
Age, Continuous	44.4 Years STANDARD_DEVIATION 14.06 • n=5 Participants	46.0 Years STANDARD_DEVIATION 13.64 • n=7 Participants	45.2 Years STANDARD_DEVIATION 13.82 • n=5 Participants
Sex: Female, Male Female	33 Participants n=5 Participants	33 Participants n=7 Participants	66 Participants n=5 Participants
Sex: Female, Male Male	27 Participants n=5 Participants	27 Participants n=7 Participants	54 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=5 Participants	11 Participants n=7 Participants	15 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	52 Participants n=5 Participants	43 Participants n=7 Participants	95 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	6 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	12 Participants n=5 Participants	7 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	45 Participants n=5 Participants	49 Participants n=7 Participants	94 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants

PRIMARY outcome

Timeframe: From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.

Population: Full analysis set (FAS): All patients randomised were analysed in the treatment group to which they were randomised regardless of whether they took study medication. This followed the intent-to-treat principle.

Outcome measures

Outcome measures
Measure	Dabigatran Etexilate n=60 Participants Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=60 Participants Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Percentage of Participants With Composite of Venous Thrombotic Event (VTE) or Major Bleeding Event (MBE) According to International Society on Thrombosis and Haemostasis (ISTH) Criteria in Full Observation Period.	1.7 Percentage of participants Interval 0.0 to 8.9	3.3 Percentage of participants Interval 0.4 to 11.5

SECONDARY outcome

Timeframe: From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.

Population: FAS, Magnetic resonance imaging (MRI), Computed tomography (CT)

VTE criterions: * New neurological signs/symptoms or worsening of previous signs/symptoms with new CVT on neuroimaging. * DVT of any limb was documented by: Abnormal compression ultrasonography; An intraluminal filling defect on venography; At autopsy * Splanchnic vein thrombosis: The presence of endoluminal material/absence of flow in the extrahepatic portal veins/mesenteric veins as shown by duplex-Doppler ultrasound/contrast-enhanced CT scan/MRI. * PE was documented by: An intraluminal filling defect in segmental/more proximal branches on spiral CT scan; An intraluminal filling defect/an extension of an existing defect/a sudden cut-off of vessels\>2.5 mm in diameter on the pulmonary angiogram; Perfusion defect of at least 75% of a segment with a local normal ventilation result on ventilation/perfusion lung scan; Inconclusive spiral CT, pulmonary angiography/lung scintigraphy with demonstration of DVT in the lower extremities by compression ultrasonography/venography; At autopsy.

Outcome measures

Outcome measures
Measure	Dabigatran Etexilate n=60 Participants Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=60 Participants Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Percentage of Participants With Recurring Cerebral Venous and Dural Sinus Thrombosis; DVT of Any Limb, PE or Splanchnic Vein Thrombosis in Full Observation Period Recurring CVT	0.0 Percentage of participants Interval 0.0 to 6.0	0.0 Percentage of participants Interval 0.0 to 6.0
Percentage of Participants With Recurring Cerebral Venous and Dural Sinus Thrombosis; DVT of Any Limb, PE or Splanchnic Vein Thrombosis in Full Observation Period DVT of any limb	0.0 Percentage of participants Interval 0.0 to 6.0	0.0 Percentage of participants Interval 0.0 to 6.0
Percentage of Participants With Recurring Cerebral Venous and Dural Sinus Thrombosis; DVT of Any Limb, PE or Splanchnic Vein Thrombosis in Full Observation Period PE	0.0 Percentage of participants Interval 0.0 to 6.0	0.0 Percentage of participants Interval 0.0 to 6.0
Percentage of Participants With Recurring Cerebral Venous and Dural Sinus Thrombosis; DVT of Any Limb, PE or Splanchnic Vein Thrombosis in Full Observation Period Splanchnic vein thrombosis	0.0 Percentage of participants Interval 0.0 to 6.0	0.0 Percentage of participants Interval 0.0 to 6.0

SECONDARY outcome

Timeframe: Baseline and week 24

Population: FAS - Patients with missing/not analysable MRI scan at baseline or end of treatment (EOT) are excluded from the analysis

Cerebral venous recanalisation was assessed by imaging and was adjudicated. Occlusion of cerebral veins and sinuses was scored as: 1 = full occlusion; 0 = no occlusion/partial occlusion. This score was applied using the below conventions: Superior sagittal, straight, cavernous sinuses, left and right jugular veins each scored individually as either 0 or 1; Right lateral transverse and sigmoid sinus were scored together, Left lateral transverse and sigmoid sinus were scored together, Superior petrous sinus and inferior petrous sinus were scored together; Deep venous system, Superficial cortical veins, Cerebellar veins were scored as systems. For each patient a total score was calculated at baseline and at EOT and the recanalisation score was calculated as EOT - baseline total scores with conventions as 0 = no cerebral veins or sinuses fully occluded and 11 = all cerebral veins and sinuses fully occluded; the lower the score, the better.

Outcome measures

Outcome measures
Measure	Dabigatran Etexilate n=55 Participants Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=52 Participants Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Cerebral Venous Recanalisation as Measured by the Change in Number of Occluded Cerebral Veins and Sinuses at Week 24	-0.8 Units on scale Standard Deviation 0.78	-1.0 Units on scale Standard Deviation 0.92

SECONDARY outcome

Timeframe: From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.

Population: TS

Major bleeds were defined according to the ISTH definition of a major bleed, as follows: * Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or * Bleeding associated with a reduction in haemoglobin of at least 2 grams/deciLitre (1.24 millimole/Litre) within 24 h, or leading to transfusion of 2 or more units of blood or packed cells and/or * Fatal bleed

Outcome measures

Outcome measures
Measure	Dabigatran Etexilate n=60 Participants Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=60 Participants Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Percentage of Participants With Major Bleeding According to ISTH Criteria in Full Observation Period	1.7 Percentage of participants Interval 0.0 to 8.9	3.3 Percentage of participants Interval 0.4 to 11.5

SECONDARY outcome

Timeframe: From first administration of trial medication until end of treatment visit, up to 24 weeks.

Population: TS - Patients with missing/not analysable MRI scan at baseline or EOT are excluded from the analysis

Intracranial haemorrhage (ICH) comprised the subtypes of intracerebral bleeds, subdural bleeds, epidural bleeds and subarachnoid bleeds that were recorded.

Outcome measures

Outcome measures
Measure	Dabigatran Etexilate n=56 Participants Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=53 Participants Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Composite Endpoint of Percentage of Participants With New Intracranial Haemorrhage or Worsening of the Haemorrhagic Component of a Previous Lesion After up to 24 Weeks	1.8 Percentage of participants Interval 0.0 to 9.6	3.8 Percentage of participants Interval 0.5 to 13.0

SECONDARY outcome

Timeframe: From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.

Population: TS

A clinically relevant non-major bleeding event (CRNMBE) was a clinically overt bleed that did not meet the criteria for a major bleed but prompted a clinical response, in that it led to at least 1 of the following: A hospital admission (i.e. overnight stay in the hospital) for bleeding / A physician guided medical or surgical treatment for bleeding / A physician guided change, interruption or discontinuation of trial medication.

Outcome measures

Outcome measures
Measure	Dabigatran Etexilate n=60 Participants Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=60 Participants Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Percentage of Participants With Clinically Relevant Non-major Bleeding Events in Full Observation Period.	0.0 Percentage of participants Interval 0.0 to 6.0	1.7 Percentage of participants Interval 0.0 to 8.9

SECONDARY outcome

Timeframe: From first administration of trial medication until end of treatment visit, up to 24 weeks.

Population: TS

Percentage of participants with major bleeding according to ISTH criteria or CRNMBEs after up to 24 weeks.

Outcome measures

Outcome measures
Measure	Dabigatran Etexilate n=60 Participants Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=60 Participants Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Percentage of Participants With Major Bleeding According to ISTH Criteria or CRNMBEs After up to 24 Weeks	1.7 Percentage of participants Interval 0.0 to 8.9	5.0 Percentage of participants Interval 1.0 to 13.9

SECONDARY outcome

Timeframe: From first administration of trial medication until end of treatment visit, up to 24 weeks.

Population: TS

Percentage of participants with any bleeding event after up to 24 weeks where any bleeding event is the sum of all major and non-major bleeding events.

Outcome measures

Outcome measures
Measure	Dabigatran Etexilate n=60 Participants Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=60 Participants Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Percentage of Participants With Any Bleeding Event After up to 24 Weeks	20.0 Percentage of participants Interval 10.8 to 32.3	20.0 Percentage of participants Interval 10.8 to 32.3

Adverse Events

Dabigatran Etexilate

Serious events: 8 serious events

Other events: 21 other events

Deaths: 0 deaths

Warfarin

Serious events: 6 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Dabigatran Etexilate n=60 participants at risk Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=60 participants at risk Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Gastrointestinal disorders Diarrhoea	6.7% 4/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	3.3% 2/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Gastrointestinal disorders Dyspepsia	6.7% 4/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Nervous system disorders Headache	16.7% 10/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	13.3% 8/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Psychiatric disorders Depression	3.3% 2/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	6.7% 4/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Psychiatric disorders Insomnia	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	6.7% 4/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Respiratory, thoracic and mediastinal disorders Cough	8.3% 5/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Dabigatran Etexilate n=60 participants at risk Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.	Warfarin n=60 participants at risk Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
Infections and infestations Pyelonephritis	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Infections and infestations Severe fever with thrombocytopenia syndrome	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Infections and infestations Urinary tract infection	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Meningioma	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Blood and lymphatic system disorders Evans syndrome	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Nervous system disorders Cerebral haemorrhage	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Nervous system disorders Cerebral infarction	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Nervous system disorders Epilepsy	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Nervous system disorders Intracranial aneurysm	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Nervous system disorders Intracranial pressure increased	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Nervous system disorders Intracranial venous sinus thrombosis	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Nervous system disorders Paraesthesia	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Nervous system disorders Seizure	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Eye disorders Glaucoma	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Vascular disorders Raynaud's phenomenon	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Gastrointestinal disorders Gastrointestinal necrosis	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Gastrointestinal disorders Intestinal haematoma	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Gastrointestinal disorders Vomiting	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Investigations International normalised ratio fluctuation	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	3.3% 2/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS	1.7% 1/60 • From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. TS